Neoplasms and cancer are abnormal growths of cells. Cancer cells rapidly reproduce despite restriction of space, nutrients shared by other cells, or signals sent from the body to stop reproduction. Cancer cells are often shaped differently from healthy cells, do not function properly, and can spread into many areas of the body. Abnormal growths of tissue, called tumours, are clusters of cells that are capable of growing and dividing uncontrollably. Tumours can be benign (noncancerous) or malignant (cancerous). Benign tumours tend to grow slowly and do not spread. Malignant tumours can grow rapidly, invade and destroy nearby normal tissues, and spread throughout the body. Malignant cancers can be both locally invasive and metastatic.
IL-18 (Interleukin-18) is a proinflammatory cytokine of the IL-1 superfamily. It was originally identified as being produced by macrophages in response to microbial lipopolysaccharide during infection. IL-18 binds to the IL-18 receptor (IL-18R), stimulating activation of other inflammatory cytokines such as IL-12, TNF-α, and IFN-γ. The role of IL-18 has also been studied in relation to tumour biology, and increases in its expression have been shown to exert antitumour effects in mouse and cell line models (e.g. Lebel-Binay et al. (2003). Int J. Cancer 106, 827-835), possibly through induction of other proteins that induce tumour cell death, or through antiangiogenic properties.
Available immunoreagents specifically detect the monomeric form of IL-18, and they cannot be used to reliably diagnose cancer since the data they provide concerning monomeric IL-18 expression levels in cancer are inconsistent and often contradictory. In human tumours, some studies have suggested that monomeric IL-18 is moderately increased in non-small cell lung cancer, and that prostate tumours with a high proportion of cells staining positive for monomeric IL-18 had better prognosis. However, investigation of correlation between monomeric IL-18 levels and metastases has been less consistent. Okamoto and co-workers (Okamoto et al. (2009) Internal Medicine 48, 763-773) showed a modest but statistically significant increase in serum monomeric IL-18 from lung cancer patients with bone metastases, and Lissoni et al. (Lissoni et al. (2000). J Biol. Regul. Homeost. Agents, 14, 275-277) showed a similar result for lung cancer patients with stage IV (metastatic) disease. However, in colon cancer, reduced monomeric IL-18 levels correlated with distal metastases and poor prognosis (Pages et al. (1999) Int. J. Cancer 84, 326-330).
One important finding with implications for monitoring of IL-18 in disease is that alternative forms of IL-18 protein have been detected in human sera. These relate to homodimer (dimeric) and multimer (multimeric) complexes of IL-18 which form due to unusually strong disulphide bonds created between pairs of IL-18 molecules, and are readily detectable even in solutions of purified recombinant IL-18. It has been reported that the concentration of dimeric IL-18 in serum is up to 100-fold higher than the active, monomeric form (Seya et al. (2001) Int. J. Mol. Medicine 8, 585-590). Commercially available antibodies and immunoassays for detection of IL-18 only recognise the 18 kDa monomeric ligand or the 24 kDa pro-form monomer. They do not recognise dimeric IL-18 which appears to account for the majority of IL-18 in serum (Shida et al. (2001) J. Immunol. 166, 6671-6679).
Given the conflicting reports in the literature and the limitations of available reagents for detecting dimeric IL-18, current clinical data regarding the significance of IL-18 levels in various disease conditions, particularly serum IL-18, must be interpreted with caution.
There is a need for improved methods for the screening, diagnosis, prognostication and treatment of cancer, and a better understanding of the role of IL-18 as a biomarker of cancer and cancer metastasis.